tbuckley/cabot-search huggingface dataset:
Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis
Authors: Guy Jerusalem, Yeon Hee Park, Toshinari Yamashita, Sara A. Hurvitz, Shanu Modi, Fabrice Andre, Ian E. Krop, Xavier Gonzàlez Farré, Benoit You, Cristina Saura, Sung-Bae Kim, Cynthia R. Osborne, Rashmi K. Murthy, Lorenzo Gianni, Toshimi Takano, Yali Liu, Jillian Cathcart, Caleb Lee, Christophe Perrin
Journal: Cancer Discovery (2022)

Abstract DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%–77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7–18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. Significance: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711
Errors in Tables 1 and 2
Journal: JAMA Network Open (2022)

Jumpei Yoshimura, MD; Kazuma Yamakawa, MD, PhD; Yoshinori Ohta, MD, PhD; Kensuke Nakamura, MD, PhD; Hideki Hashimoto, MD, PhD; Masahiro Kawada, MD; Hiroki Takahashi, MD; Takeshi Yamagiwa, MD, PhD; Akira Kodate, MD; Kyohei Miyamoto, MD, PhD; Satoshi Fujimi, MD, PhD; Takeshi Morimoto, MD, PhD, MPH
Glutamine synthetase limits β-catenin–mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1
Authors: Weiwei Dai, Jianliang Shen, Junrong Yan, Alex J. Bott, Sara Maimouni, Heineken Q. Daguplo, Yujue Wang, Khoosheh Khayati, Jessie Yanxiang Guo, Lanjing Zhang, Yongbo Wang, Alexander Valvezan, Wen-Xing Ding, Xin Chen, Xiaoyang Su, Shenglan Gao, Wei-Xing Zong
Journal: Journal of Clinical Investigation (2022)

Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS's ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.
Performance of lipid fingerprint by routine matrix-assisted laser desorption/ionization time of flight for the diagnosis of Mycobacterium tuberculosis complex species
Authors: Ximena Gonzalo, Shih Yrah, Agnieszka Broda, Ian Laurenson, Pauline Claxton, Markus Kostrzewa, Francis Drobniewski, Gerald Larrouy-Maumus
Journal: Clinical Microbiology and Infection (2022)

Rapid detection of bacterial pathogens at species and sub-species levels is crucial for appropriate treatment, infection control, and public health management. Currently, one of the challenges in clinical microbiology is the discrimination of mycobacterial sub-species within the M. tuberculosis complex (MTBC). Our objective was to evaluate the ability of a biosafe mycobacterial lipid-based approach to identify MTBC cultures and sub-species.A blinded study was conducted using 90 mycobacterial clinical isolate strains comprising MTBC strains sub-cultured in Middlebrook 7H11 medium supplemented with 10% oleic-acid, dextrose, catalase growth supplement and incubated for up to 6 weeks at 37°C and using the following seven reference strains (M. tuberculosis H37Rv, M canettii, M. africanum, M. pinnipedii, M. caprae, M. bovis, and M. bovis BCG) grown under the same conditions, to set the reference lipid database and test it against the 90 MTBC clinical isolates. Cultured mycobacteria were heat-inactivated and loaded onto the matrix-assisted laser desorption/ionization target followed by the addition of the matrix. Acquisition of the data was performed using the positive ion mode.Based on the identification of clear and defined lipid signatures from the seven reference strains, the method that we developed was fast (<10 minutes) and produced interpretable profiles for all but four isolates, caused by poor ionization giving an n = 86 with interpretable spectra. The sensitivity and specificity of the matrix-assisted laser desorption/ionization time of flight were 94.4 (95% CI, 86.4-98.5) and 94.4 (95% CI, 72.7-99.9), respectively.Mycobacterial lipid profiling provides a means of rapid, safe, and accurate discrimination of species within the MTBC.
203Pb-VMT-α-NET Scintigraphy of a Patient With Neuroendocrine Tumor
Authors: Dirk Müller, Hendrik Herrmann, Michael K. Schultz, Christoph Solbach, Thomas Ettrich, Vikas Prasad
Journal: Clinical Nuclear Medicine (2022)

Abstract In an end-stage midgut neuroendocrine tumor patient with carcinoid heart disease, right ventricular dysfunction, mildly reduced renal function, and refractory to 6 cycles of 177 Lu-HA-DOTATATE therapy, planar, and 22 hours SPECT/CT images were acquired after injection of 224 MBq of 203 Pb-VMT-α-NET to assess the feasibility of performing 212 Pb-VMT-α-NET therapy. A comparison of the 1.5 and 22 hours SPECT/CT images with 68 Ga-HA-DOTATATE PET/CT showed high uptake of 203 Pb-VMT-α-NET in liver metastases matching with the results of the PET/CT investigation.
Enhancing Clinical Diagnosis for Patients With Persistent Pulmonary Abnormalities After COVID-19 Infection
Authors: Anna Sviridenko, Anna Boehm, Gianpaolo di Santo, Christian Uprimny, Bernhard Nilica, Josef Fritz, Frederik L. Giesel, Uwe Haberkorn, Sabina Sahanic, Clemens Decristoforo, Ivan Tancevski, Gerlig Widmann, Judith Loeffler-Ragg, Irene Virgolini
Journal: Clinical Nuclear Medicine (2022)

Abstract Coronavirus disease 2019 (COVID-19)–related pneumonia challenges clinical practice. We explore the potential diagnostic benefit of PET/CT to establish the underlying inflammatory or fibrotic repair processes in prolonged structural lung abnormalities in COVID-19 patients. Patients and Methods Six post COVID-19 patients suspected for pulmonary fibrosis were scheduled for dual-tracer PET/CT with 18 F-FDG and 68 Ga–fibroblast activation protein inhibitor (FAPI)–46. The uptake of 68 Ga-FAPI-46 in the involved lung was compared with a control group of 9 non–COVID-19 patients. Clinical data and PET/CT imaging were collected and analyzed. Results PET/CT revealed in all 6 pulmonary impaired patients the reduced glucose avidity on 18 F-FDG and clear positivity on 68 Ga-FAPI-46 PET/CT in comparison to the control group. Conclusions Enhancing fibrotic repair mechanisms, 68 Ga-FAPI PET/CT may improve noninvasive clinical diagnostic performance in patients with long-term CT abnormalities after severe COVID-19. Although this study shows promising results, additional studies in larger populations are required to establish a general diagnostic guideline.
A return to austerity will further damage the public’s health
Authors: Michael Marmot
Journal: BMJ (2022)

<h3>ABSTRACT</h3> Zika virus can be passed from a pregnant woman to her fetus, thus leading to birth defects including more than microcephaly. It has been recently estimated that one-third of the world population will be infected by Zika, but unfortunately no vaccine or medicine is available so far. Zika NS2B-NS3pro is essential for its replication and thus represents an attractive target for drug discovery/design. Here we characterized conformation, catalysis, inhibition and dynamics of linked and unlinked Zika NS2B-NS3pro complexes by both experiments and MD simulations. The results unveil the unique properties of Zika NS2B-NS3pro which are very different from Dengue one. Particularly, CD and NMR studies indicate that unlike Dengue, the C-terminal region of Zika NS2B with a significant sequence variation is highly disordered in the open conformation. Indeed, MD simulations reveal that up to 100 ns, the Dengue NS2B C-terminus constantly has close contacts with its NS3pro domain. By a sharp contrast, the Zika NS2B C-terminus loses the contacts with its NS3pro domain after 10 ns, further forming a short β-sheet characteristic of the closed conformation at 30 ns. Furthermore, we found that a small molecule, previously identified as an active site inhibitor for other flaviviral NS2B-NS3pro, inhibited Zika NS2B-NS3pro potently in an allosteric manner. Our study provides the first insight into the dynamics of Zika NS2B-NS3pro and further deciphers that it is susceptible to allosteric inhibition, which thus bears critical implications for the future development of therapeutic allosteric inhibitors.
Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals
Authors: Luca M. Zaeck, Mart M. Lamers, Babs E. Verstrepen, Theo M. Bestebroer, Martin E. van Royen, Hannelore Götz, Marc C. Shamier, Leanne P. M. van Leeuwen, Katharina S. Schmitz, Kimberley Alblas, Suzanne van Efferen, Susanne Bogers, Sandra Scherbeijn, Guus F. Rimmelzwaan, Eric C. M. van Gorp, Marion P. G. Koopmans, Bart L. Haagmans, Corine H. GeurtsvanKessel, Rory D. de Vries
Journal: Nature Medicine (2022)

In July 2022, the ongoing monkeypox (MPX) outbreak was declared a public health emergency of international concern. Modified vaccinia Ankara-Bavarian Nordic (MVA-BN, also known as Imvamune, JYNNEOS or Imvanex) is a third-generation smallpox vaccine that is authorized and in use as a vaccine against MPX. To date, there are no data showing MPX virus (MPXV)-neutralizing antibodies in vaccinated individuals nor vaccine efficacy against MPX. Here we show that MPXV-neutralizing antibodies can be detected after MPXV infection and after historic smallpox vaccination. However, a two-shot MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV-neutralizing antibodies. Dose-sparing of an MVA-based influenza vaccine leads to lower MPXV-neutralizing antibody levels, whereas a third vaccination with the same MVA-based vaccine significantly boosts the antibody response. As the role of MPXV-neutralizing antibodies as a correlate of protection against disease and transmissibility is currently unclear, we conclude that cohort studies following vaccinated individuals are necessary to assess vaccine efficacy in at-risk populations.
Right Ventricular Limitation: A Tale of Two Elastances
Authors: Sheldon Magder, Douglas Slobod, Nawaporn Assanangkornchai
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Right ventricular (RV) dysfunction is a commonly considered cause of low cardiac output in critically ill patients. Its management can be difficult and requires an understanding of how the RV limits cardiac output. We explain that RV stroke output is caught between the passive elastance of the RV walls during diastolic filling and the active elastance produced by the RV in systole. These two elastances limit RV filling and stroke volume and consequently limit left ventricular stroke volume. We emphasize the use of the term "RV limitation" and argue that limitation of RV filling is the primary pathophysiological process by which the RV causes hemodynamic instability. Importantly, RV limitation can be present even when RV function is normal. We use the term "RV dysfunction" to indicate that RV end-systolic elastance is depressed or diastolic elastance is increased. When RV dysfunction is present, RV limitation occurs at lowerpulmonary valve opening pressures and lower stroke volume, but stroke volume and cardiac output still can be maintained until RV filling is limited. We use the term "RV failure" to indicate the condition in which RV output is insufficient for tissue needs. We discuss the physiological underpinnings of these terms and implications for clinical management.
Intermediate- to long-term outcomes of endoscopic transpapillary gallbladder stenting in patients with gallstone-related disease: a 10-year single-center experience
Authors: Wiriyaporn Ridtitid, Natee Faknak, Panida Piyachaturawat, Nicha Teeratorn, Yingluk Sritunyarat, Phonthep Angsuwatcharakon, Parit Mekaroonkamol, Pradermchai Kongkam, Rungsun Rerknimitr
Journal: Endoscopy (2022)

Endoscopic transpapillary gallbladder stenting (ETGS) can be a bridging therapy to elective cholecystectomy or a permanent gallbladder drainage method in patients with symptomatic gallbladder disease who are awaiting cholecystectomy or are unfit for surgery, respectively. We evaluated the intermediate- to long-term outcomes of ETGS in these groups.We retrospectively reviewed 234 patients (acute cholecystitis = 147), who were unfit for surgery (n = 50) or had deferred cholecystectomy (n = 184) and who underwent ETGS between 2012 and 2021. A 7-Fr, 15-cm, double-pigtail plastic stent was placed for ETGS without scheduled stent exchange. Biliary event-free rates (i. e. cholecystitis and cholangitis) were determined at 6 months, 1 year, and ≥ 2 years.Technical and clinical success rates were 84.6 % (198/234) and 97.4 % (193/198), respectively. Kaplan-Meier analysis (n = 193) showed a biliary event-free rate of 99 % (95 %CI 0.95-1.00) at 6 months, 92 % (95 %CI 0.87-0.97) at 1 year, and 76 % (95 %CI 0.65-0.93) at ≥ 2 years, during a median follow-up period of 564 days (range 200-3001 days).ETGS is an effective biliary drainage method that should be considered in selected cases with common bile duct stone where cholecystectomy could not be performed or was deferred. The biliary event-free rates of ≥ 76 % up to ≥ 2 years further support the use of ETGS in these patient groups.
The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer
Authors: James E. Barrett, Karin Sundström, Allison Jones, Iona Evans, Jiangrong Wang, Chiara Herzog, Joakim Dillner, Martin Widschwendter
Journal: Genome Medicine (2022)

Abstract Background Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. Methods We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1–4 years and 218 remained disease-free. Results We developed the WID-CIN (Women’s cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88–0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3–96.1) in all and 92.7% (85.9–99.6) and 65.6% (49.2–82.1) in women aged ≥30 and &lt;30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0–61.5) cases developing 1–4 years after sample donation in all ages or 56.9% (47.6–66.2) and 53.5% (43.7–63.2) in ≥30 and &lt;30-year-old women, at a specificity of 75%. Conclusions The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future.
Optimal Timing of a Physical Exercise Intervention to Improve Cardiorespiratory Fitness
Authors: Gabriela G.F. van der Schoot, Harm L. Ormel, Nico-Derk L. Westerink, Anne M. May, Sjoerd G. Elias, Yoran M. Hummel, Joop D. Lefrandt, Peter van der Meer, Joost P. van Melle, Boelo J. Poppema, Joyce M.A. Stel, Annette W.G. van der Velden, Aline H. Vrieling, Johan B. Wempe, Marcel G. ten Wolde, Marcel Nijland, Elisabeth G.E. de Vries, Jourik A. Gietema, Annemiek M.E. Walenkamp
Journal: JACC CardioOncology (2022)

Despite the widely acknowledged benefit of exercise for patients with cancer, little evidence on the optimal timing of exercise on adverse effects of cancer treatment is available.The aim of this study was to determine whether an exercise intervention initiated during chemotherapy is superior to an intervention initiated after chemotherapy for improving long-term cardiorespiratory fitness (peak oxygen uptake [VO2peak]).In this prospective, randomized clinical trial, patients scheduled to receive curative chemotherapy were randomized to a 24-week exercise intervention, initiated either during chemotherapy (group A) or afterward (group B). The primary endpoint was VO2peak 1 year postintervention. Secondary endpoints were VO2peak postintervention, muscle strength, health-related quality of life (HRQoL), fatigue, physical activity, and self-efficacy. Between-group differences were calculated using intention-to-treat linear mixed-models analyses.A total of 266 patients with breast (n = 139), testicular (n = 95), and colon cancer (n = 30) as well as lymphoma (n = 2) were included. VO2peak immediately postintervention and 1 year postintervention did not differ between the 2 groups. Immediately postchemotherapy, patients in group A exhibited significantly lower decreases in VO2peak (3.1 mL/kg/min; 95% CI: 2.2-4.0 mL/kg/min), HRQoL, and muscle strength and reported less fatigue and more physical activity than those in group B.Exercise can be safely performed during chemotherapy and prevents fatigue and decreases in VO2peak, muscle strength, and HRQoL, in addition to hastening the return of function after chemotherapy. Also, if exercise cannot be performed during chemotherapy, a program afterward can enable patients to regain the same level of function, measured 1 year after completion of the intervention. (Optimal Timing of Physical Activity in Cancer Treatment [ACT]; NCT01642680).
Risk of reinfection, vaccine protection, and severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark
Authors: Christian Holm Hansen, Nikolaj Ulrik Friis, Peter Bager, Marc Stegger, Jannik Fonager, Anders Fomsgaard, Mie Agermose Gram, Lasse Engbo Christiansen, Steen Ethelberg, Rebecca Legarth, Tyra Grove Krause, Henrik Ullum, Palle Valentiner-Branth
Journal: The Lancet Infectious Diseases (2022)
COP27 Climate Change Conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Robert Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: The Lancet Microbe (2022)
COP27 Climate Change Conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Robert Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: The Lancet HIV (2022)
COP27 Climate Change Conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Robert Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: The Lancet Diabetes & Endocrinology (2022)
COP27 Climate Change Conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Robert Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: The Lancet Digital Health (2022)
COP27 Climate Change Conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Robert Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: The Lancet Healthy Longevity (2022)
COP27 Climate Change Conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Robert Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: The Lancet Infectious Diseases (2022)